William Becker1, Haider Rasheed Alrafas1, Philip B Busbee1, Michael D Walla2, Kiesha Wilson1, Kathryn Miranda1, Guoshuai Cai3, Vasanta Putluri4, Nagireddy Putluri4, Mitzi Nagarkatti1, Prakash S Nagarkatti1. 1. Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC, USA. 2. Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC, USA. 3. Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA. 4. Dan L. Duncan Cancer Center, Advanced Technology Core, Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, TX, USA.
Abstract
BACKGROUND AND AIMS: Cannabinoid receptor [CB] activation can attenuate inflammatory bowel disease [IBD] in experimental models and human cohorts. However, the roles of the microbiome, metabolome, and the respective contributions of haematopoietic and non-haematopoietic cells in the anti-colitic effects of cannabinoids have yet to be determined. METHODS: Female C57BL/6 mice were treated with either cannabidiol [CBD], Δ 9-tetrahydrocannabinol [THC], a combination of CBD and THC, or vehicle, in several models of chemically induced colitis. Clinical parameters of colitis were assessed by colonoscopy, histology, flow cytometry, and detection of serum biomarkers; single-cell RNA sequencing and qRT-PCR were used to evaluate the effects of cannabinoids on enterocytes. Immune cell transfer from CB2 knockout mice was used to evaluate the contribution of haematopoietic and non-haematopoietic cells to colitis protection. RESULTS: We found that THC prevented colitis and that CBD, at the dose tested, provided little benefit to the amelioration of colitis, nor when added synergistically with THC. THC increased colonic barrier integrity by stimulating mucus and tight junction and antimicrobial peptide production, and these effects were specific to the large intestine. THC increased colonic Gram-negative bacteria, but the anti-colitic effects of THC were independent of the microbiome. THC acted both on immune cells via CB2 and on enterocytes, to attenuate colitis. CONCLUSIONS: Our findings demonstrate how cannabinoid receptor activation on both immune cells and colonocytes is critical to prevent colonic inflammation. These studies also suggest how cannabinoid receptor activation can be used as a preventive and therapeutic modality against colitis.
BACKGROUND AND AIMS: Cannabinoid receptor [CB] activation can attenuate inflammatory bowel disease [IBD] in experimental models and human cohorts. However, the roles of the microbiome, metabolome, and the respective contributions of haematopoietic and non-haematopoietic cells in the anti-colitic effects of cannabinoids have yet to be determined. METHODS: Female C57BL/6 mice were treated with either cannabidiol [CBD], Δ 9-tetrahydrocannabinol [THC], a combination of CBD and THC, or vehicle, in several models of chemically induced colitis. Clinical parameters of colitis were assessed by colonoscopy, histology, flow cytometry, and detection of serum biomarkers; single-cell RNA sequencing and qRT-PCR were used to evaluate the effects of cannabinoids on enterocytes. Immune cell transfer from CB2 knockout mice was used to evaluate the contribution of haematopoietic and non-haematopoietic cells to colitis protection. RESULTS: We found that THC prevented colitis and that CBD, at the dose tested, provided little benefit to the amelioration of colitis, nor when added synergistically with THC. THC increased colonic barrier integrity by stimulating mucus and tight junction and antimicrobial peptide production, and these effects were specific to the large intestine. THC increased colonic Gram-negative bacteria, but the anti-colitic effects of THC were independent of the microbiome. THC acted both on immune cells via CB2 and on enterocytes, to attenuate colitis. CONCLUSIONS: Our findings demonstrate how cannabinoid receptor activation on both immune cells and colonocytes is critical to prevent colonic inflammation. These studies also suggest how cannabinoid receptor activation can be used as a preventive and therapeutic modality against colitis.
Authors: Stephanie Coward; Fiona Clement; Eric I Benchimol; Charles N Bernstein; J Antonio Avina-Zubieta; Alain Bitton; Mathew W Carroll; Glen Hazlewood; Kevan Jacobson; Susan Jelinski; Rob Deardon; Jennifer L Jones; M Ellen Kuenzig; Desmond Leddin; Kerry A McBrien; Sanjay K Murthy; Geoffrey C Nguyen; Anthony R Otley; Remo Panaccione; Ali Rezaie; Greg Rosenfeld; Juan Nicolás Peña-Sánchez; Harminder Singh; Laura E Targownik; Gilaad G Kaplan Journal: Gastroenterology Date: 2019-01-10 Impact factor: 22.682
Authors: Sean R Llewellyn; Graham J Britton; Eduardo J Contijoch; Olivia H Vennaro; Arthur Mortha; Jean-Frederic Colombel; Ari Grinspan; Jose C Clemente; Miriam Merad; Jeremiah J Faith Journal: Gastroenterology Date: 2017-11-23 Impact factor: 22.682